Earlier this year, when Germans were cracking open boxes of chocolate muesli—a common breakfast cereal in their country—it’s unlikely their thoughts slid to the chemical 4-methylbenzophenone, much less to the fact that this component of printing ink had slipped from the outside of the cardboard box and into the cereal. That is, until the European Food Safety Authority (EFSA) was asked to look into the matter.
Open a cereal box or a carton of juice, breathe in an asthma drug from an inhaler, or pop an antihistamine pill out of a plastic pouch’s metal foil. You are probably thinking about the product you’re about to consume and not about its packaging—except, perhaps, for a twinge of regret about contributing to landfill waste. But here’s something to keep in mind: Even when the wrapping comes off, you inevitably ingest some of the container.
Plastic, rubber, cardboard, metal, and glass packaging act as a barrier against all sorts of contamination, but they are also a source of contamination. Speak with anyone who produces, studies, or regulates packaging, and you will hear this point repeated: It is not a question of whether packaging components will leach into a product, it’s a question of how much. “If you have a material in contact with food, and if it’s not completely inert—and there are no completely inert materials—something in the packaging will end up in the food,” says Dimitrios Spyropoulos, a regulator at EFSA.
The same holds true for pharmaceuticals. “You will always have leachables,” says Guirag Poochikian, a retired U.S. Food & Drug Administration regulator who used to evaluate leachables from inhaler devices. “The question is ‘What are they, and what is their safety margin’ ” in humans?
As analytical technology improves—in some cases allowing parts-per-trillion levels of detection—trace, and sometimes not-so-trace, levels of thousands of different leachables can be measured in food and pharmaceuticals. More challenging is tracking down the source of migrating compounds and figuring out what levels are harmful to human health. Controversies over what migration levels constitute harmful human exposure continue to simmer. And even as researchers come up with new strategies for reducing leachables, cases of unexpected packaging chemicals migrating into food or drug formulations point to the need for further diligence.
Packaging leachables have a daunting number of potential sources: They can originate from the molecular makeup of the container or from chemicals a container encounters during manufacturing, sterilization, or shipping.
Plastic is by far the most common packaging material—think food and pill bottles, plastic wrap, prefilled syringes that carry units of injectable drugs, or even intravenous-fluid bags.
Leachables from plastics can include everything from leftover monomer building blocks to additives used to make plastic strong or malleable. Probably the most infamous leachable from plastics is bisphenol A (BPA), which is used as a building block in polycarbonate bottles and in the epoxy-resin liners of metal cans.
Last year, the Canadian government banned the use of BPA in baby bottles as a precautionary measure against the risk that its presence could cause endocrine disruption in children—a risk that other regulatory agencies such as FDA dispute (C&EN, Nov. 17, 2008, page 42). But BPA is just one of hundreds of molecules that can migrate out of plastics. That group also includes di(2-ethylhexyl) phthalate, a potential carcinogen and endocrine disrupter that helps make plastics such as polyvinyl chloride (PVC) supple and bendable; phenolic antioxidants such as Irganox 1076; and benzophenone light stabilizers.
Glass is about as inert a packaging as can be, but the material can sometimes leach minerals or metals, particularly if it is recycled. Despite its low-leachability profile, glass containers typically require some form of a cap, which often contains rubber, arguably the most problematic source of migrating chemicals.
Rubber turns up in the seals or stoppers of glass jars used to hold both food and drugs, in elastomeric components in the valves of inhaler devices, and in stoppers at the ends of plungers found in prefilled syringes. Many rubber leachables come from chemicals used in or produced during processing, such as N-nitrosamines, which can sometimes be carcinogenic, or 2-mercaptobenzothiazole. Carbon black—effectively soot—was used as an additive to make rubber supple until the mid-1980s, when it was shown that cancer-causing polynuclear aromatic hydrocarbons leached from carbon-black-containing rubber used in products such as asthma inhalers and baby-bottle nipples, Poochikian says.
Other specialized packaging materials include the waxy wrapping that covers hamburgers or lines the inside of microwavable popcorn bags. Recently, Scott Mabury, a chemist at the University of Toronto, showed that this kind of packaging leaches polyfluoroalkyl phosphoric acids (PAPs), which are then absorbed by humans and accumulate in the body. These compounds can be metabolized in the body to perfluorinated carboxylic acids, which may be carcinogenic and hormone disrupting.
And then there is ink. Most packaging is covered with some form of print, be it branding or a bar code. Unfortunately, the chemicals used for printing have an uncanny ability to wind up in food and pharmaceuticals. Besides this year’s muesli case, millions of liters of infant formula were recalled in 2005 in Italy, Portugal, Spain, and France when another printing-ink component called isopropylthioxanthone was found in the product. Tetra Pak, the firm that supplied the formula’s packaging to Nestlé, has since phased out the chemical’s use.
Contamination such as that in the baby formula case is often caused by a manufacturing “off-set problem,” says Timothy Begley, a chemist involved in leachable evaluation at FDA. Materials such as snack-food bags or coated-paper cartons used for juice or baby formula are printed and then rolled up. But in the rolling-up process, “the printed layer comes in contact with the food-contact layer,” Begley says. “In the roll there is a transfer of ink components into the food-contact layer.” When the packaging is unrolled to make the bag, ink components can transfer to whatever is stored inside.
But ink can also percolate directly through some plastic packaging, such as prefilled syringes or IV bags. “In our experience, materials such as polypropylene and polyethylene do not pose a significant migration barrier to the low-molecular-weight ingredients of printing ink,” Michael Jahn said at the Conference on Leachables & Extractables for Pharmaceutical Products in Barcelona in May. Jahn does contract research work on leachables for specialty chemical maker Ciba, now part of BASF. In fact, ink can even migrate through two layers of packaging, noted Kumudini Nicholas, a regulator for Health Canada’s Therapeutic Products Directorate, at the same conference. She said that her agency initiated a product recall after a drug solution in a plastic pouch became contaminated with printing chemicals from the outside of a second plasticoverpouch.
Aside from the direct migration of chemicals from containers, packaging can also be exposed to problematic materials during its production, storage, and transport. The chemicals can later leach into the product stored in the container.
Consider these two seemingly intractable cases encountered by pharmaceutical companies that had packaged their liquid-protein drugs in prefilled syringes and then later found that the protein solution they hoped to sell had aggregated into clumps. In one case, a syringe manufacturer was using epoxy glue to attach the metal needle to the syringe’s barrel, said Ingrid Markovic, a regulator at FDA’s Center for Drug Evaluation & Research, at the leachables conference in Barcelona. Unfortunately, a solvent from the partially dried epoxy glue leached into the liquid-drug product, oxidized the protein, and caused it to aggregate. In the second case, a tungsten filament used to poke a hole through the tip of the syringe needle left tungsten oxide salt residue that later percolated into the liquid-drug formulation, also causing protein aggregation.
Even packaging sterilization—such as gamma radiation, steam, or ethylene oxide treatments—can introduce leachables. For example, gamma radiation is particularly notorious for severing carbon-chlorine bonds found in PVC plastics and some additives, forming breakdown products that can then percolate into food and drugs.
Shipping is also an issue, according to Steve Lovatt, a scientist with Bespak, a British manufacturer of valves for inhalers. “What was the truck shipping the day before? What if it was pesticides?” he asked at the Barcelona workshop. It’s important to check the cleanliness of the truck’s lining and any off-loaded equipment, he said.
Ultimately, “the problem in this business is that material is acquired from tertiary or quaternary sources,” Poochikian says. These distant sources supply a variety of industries, some of which may not have as stringent cleanliness requirements as the food and drug industries do. Consider pressurized metered-dose inhalers, such as those used by asthmatics. The medicine is suspended in a liquid, and the whole solution is stored in a plastic-lined metal canister that lies in contact with a valve that contains rubber. Large portions of the overall container, including the mouthpiece, are made of plastic. The pharmaceutical company is ultimately responsible for the product consumed by the patient, but the firm doesn’t typically make the packaging itself. Instead, a device manufacturer puts everything together, after sourcing the plastic, rubber, and metal from different companies. Chemicals used for polymerization, softening, and durability of the packaging typically come from another set of suppliers.
The logistics of placing controls throughout the supply chain can be a challenge, but spending the time to get through “the education phase” with suppliers is essential to ensure safe products, says Gerallt Williams, director of R&D at Valois Pharmaceuticals, which produces inhaler devices.
Cheryl Stults, a senior fellow at Novartis, concurs. At the Barcelona conference, she noted that during drug development it is important to consider packaging as early as possible—and definitely before starting clinical trials. “Phase III is not a time to start thinking about leachables and extractables,” she said. No one wants to have to restart product development because a packaging compound has migrated unexpectedly into the formulation and caused some sort of problem, she added.
Even when the packaging supply chain is under control, drug companies can make a small change in drug formulation that might lead to problems. For example, when a background component of a liquid drug given to people suffering from kidney problems was switched from human albumin serum to polysorbate, the polysorbate enhanced leaching of chemicals from rubber used in the packaging. These leachables were at least partially responsible for a dangerous syndrome called pure red cell aplasia, which arose in patients receiving the drug (Kidney Int. 2008, 74, 1617).
Only after leachables have been identified, quantified, and sourced does the most critical step occur: determining what levels of leachables in food or drugs pose a risk to human health. Regulatory agencies have entirely different approaches to assessing the risk in food versus pharmaceuticals.
Let’s start with food. In the U.S., the Code of Federal Regulations lists ingredients that manufacturers may use to make packaging that contacts food, including a limit of how much of the additive can be present in the packaging. If a company wants to get a new additive approved, it must figure out how much leaches out of the packaging and into the food over 30 days; further migration for the remainder of the product’s shelf life is extrapolated, Begley says. In some cases, migration is assumed to be 100%, he adds.
Allowable levels for a given packaging ingredient are based on estimating the “cumulative estimated daily intake” that a person will have of that leachable ingredient, Begley says. As the estimated intake increases, the company must provide more extensive toxicological data. Because the migration of leachables can be enhanced or hampered by the chemical nature of the product inside—whether it is, say, watery, acidic, or oily—the limits are sometimes set differently for different foods.
In the European Union, a specific list of food-allowable components exists only for plastic packaging. All other components of packaging are subject to a general rule that food-contact materials should “not transfer their constituents to food in quantities which could endanger human health,” Spyropoulos says. When evaluating the possible health risk of food-packaging constituents, EFSA assumes a consumer will eat 1 kg of food containing the ingredient in question and sets limits on the basis of toxicological concerns of that consumption.
When it comes to pharmaceuticals, governments worldwide have not made any regulations on leachables. Instead, regulators, including those in the U.S. and the EU, evaluate the risk of leachables from a new drug’s packaging on a case-by-case basis as the drug traverses regulatory approval. Although there are no set rules for drugs, some of the elements of pharmaceutical packaging evaluation are more stringent than for food. For example, FDA requires data on pharmaceutical leachables throughout the entire shelf life of the product, instead of just the 30 days for food. “Pharmaceutical companies often look to packaging components that are allowed in food as starting points for drug-packaging design,” Stults said at the conference.
When assessing the health risk of drug-packaging leachables, regulators typically triage on the basis of how often the drug will be consumed or how it will be delivered, Markovic notes. For example, leachables from drugs that are inhaled into the lungs, sniffed up the nose, or injected into the bloodstream are considered higher risk than those in a drug that is swallowed and has the relative luxury of the digestive track to protect the body from harm.
Then there is the frequency of use. Drugs taken on a daily basis are considered riskier than infrequently used drugs because any leachables present will be more regularly ingested.
Another area of concern is drugs in liquid formulations because solutions can elicit more leachables than a pill or a powder.
Because of the lack of specific regulations for pharmaceutical packaging, a working group composed of industry scientists, regulators, and academics was formed in 2001 under the auspices of the Product Quality Research Institute (PQRI). The group spent six years developing guidelines for doing extractable and leachable studies of inhalable drugs that U.S. and European regulators now endorse as a guideline—although they still reserve the right to evaluate each case individually. The guidelines establish two important thresholds for leachables in inhalable drugs.
The first is an analytical basement called the Safety Concern Threshold, below which a leachable’s presence is considered too small to worry about (0.15 μg per day). They also developed a second threshold (5 μg per day), below which any leachable is considered tolerable to humans—as long as the leachable isn’t a known toxicant or doesn’t have a chemical structure similar to one. Finally, toxicological studies must be done for any leachables present above 5 μg per day.
Another PQRI working group is now developing guidelines for leachables in ophthalmic and injectable drugs. They aim to have guidelines in a couple of years.
Generating toxicological data for a given leachable, which is expensive because it often involves animal studies, can lag behind the leachable’s identification. For example, in the case of contamination of infant formula by the ink compound isopropylthioxanthone, EFSA had to work with a limited amount of toxicological data for the compound. In the end, the agency concluded that the levels of isopropylthioxanthone didn’t pose problems to infants, but, “We said to industry that if it was going to be used, we would need more toxicological data,” EFSA’s Spyropoulos says. “Industry preferred not to use more money to do the studies but to abandon its use.”
Sometimes the limits of known leachables set by regulators are controversial, as illustrated by the debate over BPA. Scientists such as biomedical researcher Wade Welshons of the University of Missouri, Columbia, argue that their data show that both FDA’s and the European Commission’s allowable level of the molecule in food can cause endocrine disruption in humans and that regulators have been basing their decisions on just four industry-sponsored studies. Regulators and industry continue to argue that BPA is present in food packaging at levels that are safe and that they base their evaluation on sound science.
Others say that regulators approach the study of risk too narrowly. In particular, regulators evaluate the risk associated with individual leachable chemicals in isolation. This approach neglects the possibility that if humans are exposed to low doses of several chemicals that affect the same organ in the body, the combination may induce harmful effects, even if they are present below their “no-effect concentration” as individual chemicals, says Jane Muncke, a toxicologist at Switzerland-based glass-container supplier Emhart Glass. “New approaches need to be put in place to characterize whole-packaging toxicity—including printing inks, adhesives, and secondary packaging—to understand what consumers are actually being exposed to and whether there is a safety issue,” Muncke notes.
In addition, there is concern about the increasing use of nanotechnology in packaging to improve structural integrity and detect and kill microbes. Regulators lack the tools to characterize and detect such nanoscale materials as well as the materials’ impact on biological systems (C&EN, Oct. 6, 2008, page 38).
At the same time, those producing packaging are looking at ways to reduce leachables. For example, one way the rubber industry has dealt with problematic leachables is to give rubber a bath. These extraction baths take away a majority of chemicals of concern before the rubber passes on to the manufacturing stage, Valois Pharmaceuticals’ Williams says. Other firms coat rubber with polytetrafluoroethylene to block leaching or use rubber-curing agents such as peroxide that reduce leaching. Some researchers, such as Judit E. Puskas, a polymer scientist at the University of Akron, are developing thermoplastic elastomers that self-assemble by physical forces. This means there is no need to add rubber-processing chemicals that could later leach out, Puskas says.
To prevent ink leaching, some companies are developing higher molecular weight, polymerized, or cross-linked ink components. But the formulation of these decreased-migration inks is typically “a carefully preserved secret,” Jahn said at the conference in Barcelona. Other manufacturers opt to insert a metal foil layer as a physical barrier to ink migration. Although this may successfully block the migration of ink components, adhesives used to stick the foil in place may also be a source of leachables, Jahn warned.
Glass can also play an important role as a physical barrier. For example, to prevent leaching from polyethylene teraphthalate, a plastic that is sometimes used to store wine, some companies use chemical vapor deposition to add a layer of silicon oxide glass in between the plastic and the wine.
The packaging industry is also coming up with new ingredients and additives that leach less but do the same job. For example, after the EU banned the use of di(2-ethylhexyl) phthalate plasticizers in baby toys in 2005, companies developed a cornucopia of substitutes such as pentanediol diisobutyrates, cyclohexanedicarboxylic acid esters, and monostearate derivatives.
The common feature of all potential solutions to the leachables problem is that they cost money—sometimes several times the price of the components they replace. It remains to be seen whether consumers are willing to pay more for expensive packaging that reduces leaching into their food and drugs.